Transactivation of EGF receptor induced by G protein-coupled receptor stimulation : the study for signaling cascade by Angiotensin II

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Transactivation of EGF-receptor induced by AngiotensinII in rat vascular smooth muscle cells and cardiac fibroblasts : Using immunoprecipitation and Western blot analysis, AngII stimulation via type 1 AngII receptor (AT1) was found to phosphorylate EGF-R This phosphorylation was completely abolished by the pretreatment of Ca^<2+> chelating agents, Ca^<2+>/calmodulin inhibitors and tyrosine kinase inhibitors. In addition, specific inhibition of EGF-R by a dominant negative EGF-R mutant and tyrphostin AG1478 abolished the activation of extracellular signal-regulated kinase (ERK) by AT1, leading to the suppression of fibronectin (FN) gene expression by AT1. The promoter analysis using FN-CAT fusion gene revealed that AP-1 binding site was responsible for the AT1 responsiveness of FN gene. G1 retardation assay showed that the pretreatment of AG1478 inhibited AT1-stimulated binding of c-jun and c-fos to AP-1 site in FN gene. In summary, the transactivation of EGF-R induced by angiotensin II is mediated by Ca^<2+>/calmodulin-dependent tyrosine kinases. The activation of ERK and subsequent gene expression such as FN by AT1 were regulated through downstream signaling of EGF-R transactivation.